NCP26

NCP26 is a pyrazinamide-based small-molecule inhibitor of prolyl‑tRNA synthetase (ProRS), the proline-activating domain of the bifunctional human glutamyl‑prolyl‑tRNA synthetase EPRS1. It binds the ATP pocket of ProRS in a proline-uncompetitive, ATP-competitive manner and achieves sub-nanomolar affinity for human ProRS in the presence of physiological proline, unlike earlier proline-competitive chemotypes such as halofuginone.[3][5][6] In multiple myeloma models, NCP26 produces potent anti-proliferative and pro-apoptotic activity, including in cells resistant to proteasome inhibitors and immunomodulatory drugs, and remains effective in proline-rich, cytokine- and stroma-supported bone marrow microenvironments.[3] Mechanistically, ProRS inhibition by NCP26 increases uncharged tRNA levels, activates the amino acid response and integrated stress response via GCN2–eIF2α–ATF4–DDIT3 signaling, and triggers mitochondrial damage, caspase activation, cell-cycle arrest, and apoptosis in malignant cells, while showing a therapeutic window relative to normal hematopoietic cells.[3] NCP26 also exhibits potent activity against Plasmodium falciparum ProRS, where resistance maps to mutations in the ProRS adenosine-binding pocket, further validating ProRS as its primary target.[5]